APPLICANT'S ABSTRACT: The Center for the Neurobiological Investigation of Drug Abuse has been in existence for 2.5 years at the Bowman Gray School of Medicine, Wake Forest University. This application is for renewal of funding for the Center over the next 5 years. The Center has established all of the Project and Core activities proposed in the previous 2.5 year funding period. These accomplishments include: 1) development of new tropane analogs which have cocaine-like properties but differ with respect to potency and duration of action (Project 4); 2) establishment of a highly integrated Core facility for evaluation of these compounds at several different levels, including, in vitro binding and uptake assays, in vivo analysis of neurotransmitter levels and psychostimulant properties as evaluated by locomotor activity, anatomic characterization with respect to changes in brain metabolic activity, and effects on self-administration and drug discrimination analyses (Core B); 3) determination of the reinforcing properties of cocaine and cocaine-like compounds in terms of the associated effects on dopamine levels in the nucleus accumbens as measured by microdialysis; 4) determination for the first time of the firing relationship of identified neurons in the nucleus accumbens to the act of cocaine self-administration (Project 3); 5) demonstration of the effects of receptor inhibited adenylate cyclase on electrophysiological responses of cultured CNS neurons (Project 1); 6) determination of patterns of changes in several neurotransmitter levels in brains of self-administering animals following withdrawal (Projects 2 and 5); 7) determination of changes in mRNA for tyrosine hydroxylase enzyme in self-administering rats (Project 2); and 8) discovery of pre-morbid changes in positron emission tomographic (PET) analyses of brain metabolic activity in n. accumbens and caudate of moderate to heavy human cocaine abusers (Project 6-this project is no longer in the Center because of a separate application to the Human Imaging initiative by NIDA). Three new projects will investigate anatomical and metabolic changes in brain resulting from exposure and self-administration of new tropane analogs (Project 6); the molecular biological basis of epigenetic changes in dopamine receptor mRNA levels in self administering rats (Project 7); and in years 2-5 an extension of the rodent investigations on novel tropane analogs to a primate model in anticipation of human testing of these compounds is described (Project 8). In the past 2.5 years the Center has also achieved several important goals with respect to its establishment as a resource for information and guidance within the BGSM and the surrounding community on neurobiological issues in substance abuse education, prevention and treatment.